Signaling via estrogen receptors (ER) and epidermal growth factor receptors (EGFR) are critical for normal mammary gland development as well as breast cancer initiation and progression. Recent studies on rapid effects of estrogen, including our preliminary and published data, indicate that estrogen signaling is complex and may involve non-genomic pathways that facilitate cross-talk with EGFR signaling. The estrogen-like steroidal compound of red wine and grape skins, resveratrol, has been linked to cancer prevention. In ER alpha (+) breast cancer cells, resveratrol has been shown to promote growth arrest and apoptosis. Our published and preliminary data demonstrate ER isoform status-dependent resveratrol effects on breast cancer cell survival by modulation of the activity of the protooncogene Akt. The objective of this application is to elucidate the role of ER and EGFR isoforms on resveratrol-mediated breast cancer cell proliferation or arrest. The central hypothesis of this application is that signaling for breast cancer cell cycle progression or arrest by resveratrol is dependent on ER isoform status. The rationale for the proposed research is that elucidation of the role of resveratrol as a modulator of cell death or survival and proliferation is important for ascertaining a dual role for resveratrol as a breast cancer preventive and a promoter of established breast cancer. Our experimental approach for testing this hypothesis is to analyze relative cell cycle progression in a ER negative breast cancer cell line that ectopically express vector alone, ER alpha, ER beta, or both ER isoforms. Our first specific aim is to determine the activation status of ER alpha, beta, or EGFR following resveratrol treatment in the presence or absence of ER or EGFR specific inhibitors. Our second specific aim is to investigate the effect of modulating ER or EGFR activity on resveratrol-mediated cell cycle progression in the same range of cell lines. This will be achieved by analysis of the effect of resveratrol on cell cycle progression in the presence or absence of inhibitors to ER or EGFR. This timely research promises to fill the considerable gap in our current knowledge concerning the efficacy of resveratrol as a preventive for both women at high risk and survivors of breast cancer.